Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg), 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r² = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 ± 5.3% and ED50 = 0.48 ± 0.08 mg, r² = 0.94) or concentration (Emax = 78.3 ± 2.9% and EC50 = 0.59 ± 0.09 ng/ml, r² = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Hospital do Rim e HipertensãoNovartis PharmaceuticalsUNIFESP, EPM, Hospital do Rim e HipertensãoSciEL

Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients

Chronic allograft nephropathy is among the major causes of graft loss even in low-risk kidney transplant recipients and correlates with acute nephrotoxic events during the first year post-transplant. Therefore, calcineurin inhibitor-free regimens may improve patient and graft survival among recipients of living-related kidney transplants. To confirm this hypothesis, we evaluated the efficacy and safety of two calcineurin inhibitor-free regimens in 92 low-risk recipients of one-haplotype living-related kidney transplants. Immunosuppression consisted of tacrolimus, azathioprine and prednisone (group I, GI, N = 38), 2 doses of daclizumab, mycophenolate mofetil (MMF), and prednisone (GII, N = 33) and 2 doses of daclizumab, MMF, sirolimus and prednisone (GIII, N = 21). At 12 months, treatment failure (biopsy-confirmed acute rejection, graft loss or death) was higher in GII compared to GIII and GI (54.5 vs 24.0 vs 13.1%, P < 0.01, respectively). In patients of black ethnicity the incidence of acute rejection was 25 vs 83.3 vs 20% (P = 0.055), respectively. Patient and graft survival was comparable. There were no differences in mean creatinine or calculated creatinine clearance at 12 months. Overall incidence of post-transplant diabetes mellitus (3.3%) and cytomegalovirus disease (4.3%) was similar in all groups. Further development of effective calcineurin inhibitor-free regimens should exclude patients of black ethnicity and may need full-induction therapy, perhaps with depleting agents, and concentration-controlled use of sirolimus and MMF.Universidade Federal de São Paulo (UNIFESP) Hospital do Rim e Hipertensão Divisão de NefrologiaUniversidade Federal de São Paulo (UNIFESP) Departamento de PatologiaUNIFESP, Hospital do Rim e Hipertensão Divisão de NefrologiaUNIFESP, Depto. de PatologiaSciEL

Development of a protocol for the assessment of patients with pressure ulcers through telemedicine and digital images

Introduction: Pressure ulcers are frequent complications in patients with spinal cord injuries. These ulcers need an early diagnosis and a strict follow-up to prevent a more severe evolution and delays in the rehabilitation process. Unfortunately, patients do not always have access to a center specialized in the treatment of wounds, and thus, telemedicine can be useful in such cases. Objective: To evaluate the effectiveness of a protocol for the assessment of pressure ulcers through digital images. Methods: 15 patients were selected, totaling 33 ulcers. The patients were separately assessed by 2 on-site physiatrists, who filled out the first part of the protocol (patients’ clinical data) at the time of the consultation and took the photographs. These were sent to the physiatrists at-distance, who evaluated the wounds through the photographs and the data sent by the on-site physician. The similarities and differences between the two on-site physicians, between the on-site physicians and the physicians at-distance and between the two physicians at-distance were compared regarding the degree, necrosis, infection, fistula, secretion, wound border and depth aspect and conduct. The statistical analysis was based on Kappa calculations, a confidence interval and P value. Results: The highest Kappa values were observed when the on-site assessments were compared. For necrosis, degree and infection, the On-site Assessment (S) x Assessment at distance (D) Kappas were substantial and moderate. For the item conduct, the Kappa varied from weak to almost perfect. As for the evaluations of the borders, depth, secretion and fistula, there were divergences. Conclusion: The protocol is effective to assess wound necrosis, degree and infection. There is some difficulty in using the method to evaluate the border and depth aspect, secretion and fistula. The method showed to be more satisfactory for the assessment of pressure ulcers grade I and II.Introdução: As úlceras de pressão são complicações freqüentes em pacientes com lesão medular. Estas precisam de um diagnóstico precoce e um acompanhamento rigoroso para que não evoluam para um quadro mais grave e para não retardar o processo de reabilitação. Infelizmente, não é sempre que o paciente consegue acesso a um centro especializado no tratamento de feridas e, por isso, a telemedicina pode ser útil nesses casos. Objetivo: Avaliar a eficácia de um protocolo de avaliação de úlceras de pressão através de fotografias digitais. Métodos: Selecionamos 15 pacientes, totalizando 33 úlceras. Os pacientes foram avaliados por 2 médicos fisiatras presenciais, separadamente, que no momento do exame, preencheram a primeira parte do protocolo (dados clínicos do paciente) e tiraram as fotografias. Estas foram encaminhadas aos médicos fisiatras à distância, que avaliaram as feridas através das fotos e dos dados enviados pelo médico presencial. Comparamos as semelhanças e diferenças das avaliações entre os dois médicos presenciais, entre presencial e a distancia e entre os dois médicos à distância nos quesitos grau, necrose, infecção, fístula, secreção, aspecto da borda e do fundo e conduta. A Análise estatística se baseou nos cálculos de Kappa, intervalo de confiança e P valor. Resultados: Encontramos os maiores valores de Kappa quando comparamos as avaliações presenciais. Para necrose, grau e infecção, os kappas Avaliação Presencial (P) x Avaliação à distância (D) foram substantial e moderate. No item conduta, o Kappa variou de fraco a almost perfect. Nas avaliações das bordas, fundo, secreção e fístula foram encontradas divergências. Conclusão: O protocolo é eficaz para avaliar necrose, grau e infecção das úlceras. Existe dificuldade no uso do método para avaliar o aspecto de borda, fundo, secreção e fístula. Houve maior satisfação com o método para úlceras de pressão grau I e II

Randomized crossover study to assess the inter- and intrasubject variability of morning mycophenolic acid concentrations from enteric-coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic (R)) may have an impact on the variability of MPA trough (C(0 h)) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept (R)), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at -1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1-80.3) and 54.4% (40.0-86.8) for EC-MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1-72.9) and 42.8% (37.9-49.2). High MPA C(0 h) levels > 10 mu g/mL were rarely observed with both EC-MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)(0-3 h) was comparable between treatments, while MPA C(0 h) was on average 46% higher with EC-MPS. in conclusion, predose MPA trough level monitoring appears of limited value during EC-MPS and MMF therapy given the large intrasubject variability in MPA C(0 h) levels with both treatments.Novartis Pharma AG, Basel, SwitzerlandUniversidade Federal de São Paulo, Hosp Rim & Hipertensao, BR-04038002 São Paulo, BrazilNovartis Pharmaceut, Dept Translat Med, E Hanover, NJ USAUniversidade Federal de São Paulo, Hosp Rim & Hipertensao, BR-04038002 São Paulo, BrazilWeb of Scienc